Li Mengdie, Yang Yating, Chen Tangcong, Luo Yueyang, Zhang Yingqian, Liu Huanzhong, Maes Michael
Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, 610072, China.
Behav Brain Funct. 2025 Jun 15;21(1):18. doi: 10.1186/s12993-025-00280-3.
The demethylase fat mass and obesity-related associated protein (FTO) is strongly associated with depression. Aging is a risk factor for synaptic plasticity damage in the brain and leads to neurocognitive dysfunctions. FTO-dependent m6A modification plays an important role in neurodevelopment and cognitive function. However, whether FTO is associated with susceptibility to depression in different age groups remains unknown.
We subjected 3-and 12-month-old C57BL/6J male mice to chronic unpredictable mild stress (CUMS) for 6 weeks, of which 3 weeks were used for hippocampal injection of FTO knockdown adeno-associated virus 9 shRNA (FTO-KD AAV9). Finally, 36 male mice in each 3-month-old and 12-month-old groups were divided into three groups (n = 12): Sham, CUMS, and FTO-KD. After 6 weeks, we assessed behavioral deficits (depressive and anxiety-like behaviors and cognitive impairment) by behavioral tests and hippocampal neuronal damage (dendritic spine density, neuronal atrophy, and expression of proteins associated with synaptic plasticity) by molecular biochemical experiments.
The results showed that 12-month-old C57BL/6J mice were more likely to develop depression-like behavior and spatial learning and memory impairment induced by CUMS than 3-month-old mice. Chronic stress-induced depression-like behavior and cognitive impairment worsened after the FTO-KD intervention. In the hippocampus of 3- and 12-month-old mice, CUMS induced the downregulation of FTO, nerve growth factor (NGF), reelin, and synaptic plasticity-related proteins. It also caused abnormal brain-derived neurotrophic factor (BDNF)- the tropomyosin-related kinase B (TrkB) signaling, reduced density of dendritic spines, and an increased number of neuronal pyknotic nuclei, leading to neuronal disarray, which was more significant in 12-month-old animals. FTO deficiency accelerated neuronal damage in the hippocampus of 12-month-old CUMS mice.
This study provides rodent evidence that FTO deficiency may increase the susceptibility to depression in older adults by impairing hippocampal neuronal function and neuronal synaptic plasticity in an age-dependent manner. This suggests that the development of FTO activators may be an effective treatment for depression in older adults.
去甲基化酶脂肪量与肥胖相关蛋白（FTO）与抑郁症密切相关。衰老会导致大脑突触可塑性受损，进而引发神经认知功能障碍。FTO依赖性m6A修饰在神经发育和认知功能中起重要作用。然而，FTO是否与不同年龄组的抑郁症易感性相关仍不清楚。
我们对3个月和12个月大的C57BL/6J雄性小鼠进行了6周的慢性不可预测温和应激（CUMS），其中3周用于海马注射FTO基因敲低腺相关病毒9 shRNA（FTO-KD AAV9）。最后，将3个月龄和12个月龄组的36只雄性小鼠分为三组（n = 12）：假手术组、CUMS组和FTO-KD组。6周后，我们通过行为测试评估行为缺陷（抑郁样和焦虑样行为以及认知障碍），并通过分子生化实验评估海马神经元损伤（树突棘密度、神经元萎缩以及与突触可塑性相关的蛋白质表达）。
结果表明，12个月大的C57BL/6J小鼠比3个月大的小鼠更容易出现CUMS诱导的抑郁样行为以及空间学习和记忆障碍。FTO-KD干预后，慢性应激诱导的抑郁样行为和认知障碍加重。在3个月和12个月大的小鼠海马中，CUMS诱导FTO、神经生长因子（NGF）、reelin以及与突触可塑性相关的蛋白质表达下调。它还导致脑源性神经营养因子（BDNF）-原肌球蛋白相关激酶B（TrkB）信号异常，树突棘密度降低，神经元固缩核数量增加，导致神经元紊乱，这在12个月大的动物中更为明显。FTO缺乏加速了12个月大的CUMS小鼠海马中的神经元损伤。
本研究提供了啮齿动物证据，表明FTO缺乏可能通过以年龄依赖性方式损害海马神经元功能和神经元突触可塑性，增加老年人对抑郁症的易感性。这表明开发FTO激活剂可能是治疗老年人抑郁症的有效方法。
